There is increasing evidence that propensity for weight gain, adiposity and metabolic comorbidities can begin in the womb. Maternal nutrition, in particular adequate protein intake, is critical for normal fetal development and it is well established that malnutrition in utero leads to impaired fetal growth, low or high birth weight and with either phenotype, increased risk for obesity, diabetes and cardiovascular disease later in life. The protein leverage hypothesis describes a link between protein and energy intake and specifically demonstrates that protein intake is prioritized over other macronutrients. Protein deficiency therefore promotes counter regulatory mechanisms leading to adaptive increases in total energy intake until protein balance is restored. During gestation, protein demand is increase due to increases in total body protein turnover and protein deposition to the growing fetus and maternal tissues. With the increased protein demanded by gestation and without intentional dietary alteration, pregnant women may be exposing their fetus to unintentional protein restriction during gestation and this protein reduction may leverage an increase in energy intake and create an altered intrauterine environment for the fetus. While the specific mechanistic link(s) between protein sensing and energy intake have not been described, fibroblast growth factor 21 (FGF21) has been recently discovered to act as a novel endocrine signal in protein restriction with a robust increase in FGF21 and energy intake during protein dilution dietary studies. Thus the key objective of our proposal is to study the role of FGF21 as a mediator for the protein leverage hypothesis in utero. Specific Aim 1 will test the hypothesis that FGF21 will be increased in pregnant women consuming reduced protein diets during gestation. Compellingly, fibroblast growth factor receptors (FGFRs) and ?-Klotho (cofactor to FGFR which enables FGF21 activity) have been identified in human placenta. Therefore, our second objective is to study whether the metabolic effects from FGF21 (i.e. alterations in nutrient transport) on tissues expressing ?-Klotho are present in the placenta. Accordingly, our Specific Aim 2 will test the hypothesis that FGF21 will modulate nutrient transport into the placenta. The results of the proposed studies will provide important new insight into the role of FGF21 in the protein leverage hypothesis during pregnancy and the metabolic plasticity of the placenta in response to variation in maternal protein intake. Equally important, completion of the outlined training plan by the applicant will supply the field with a well-trained, translational placental researcher who can apply the skills learned through this fellowship to advance the field of future placenta and developmental programming research.